1. Field of the Invention
The present invention relates to an intermediate for the synthesis of amlodipine, to a process for the preparation thereof and to a use of the intermediate.
The invention belongs to the field of heterocyclic chemistry and, as indicated, it relates to a chemical intermediate, ethyl 3-amino-4-(2-(phthalimido)ethoxy)crotonate, to the process for the preparation thereof, and to the use thereof for the synthesis of 2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, generically known as amlodipine, a product having a therapeutical activity used as an antiischaemic and antihypertensive agent.
2. Prior Art
Patent EP 0 089 167 discloses the use of 1,4-dihydropyridines of formula I, as immediate precursors of amlodipine of formula II: 
NR1R2=protected amine group
Patent EP 0 060 674 discloses two processes for the preparation of 1,4-dihydropyridines containing in the 2 position a substituent having an amino group and having antiischaemic and antihypertensive utility. In both cases, the yields indicated are very low (xcx9c15%) and the products have to be purified by chromatography, making the industrial application thereof difficult.
Patent EP 0 089 167 discloses the preparation of various 1,4-dihydropyridines of formula I, precursors of amlodipine, following the same processes as indicated in patent EP 0 060 674:
(a) where the aminoprotector groups are benzyl, azido or phthalimido, by reacting 2-chlorobenzaldehyde (IV) with ethyl acetoacetate (V) and methyl 3-aminocrotonate (VI) 
(b) Alternatively, where the aminoprotector groups are benzyl and azido, by reacting the benzylidene derivative (VII) with the aminocrotonate (VIII), this latter being prepared xe2x80x9cin situxe2x80x9d from the corresponding ethyl acetoacetate (V) and ammonium acetate. 
In both processes the yields obtained are very low (30% and 11% respectively where the protector group is azido, NR1R2xe2x95x90N3). On the other hand, the intermediate aminocrotonates (VIII) are not isolated or characterized, since they are prepared xe2x80x9cin situxe2x80x9d from the corresponding ethyl acetoacetate (V) prior to the reaction with the benzylidene derivative (VII). No description has been found in the literature for the isolation or characterisation of these aminocrotonates (VIII). The present inventors have unsuccessfully tried to isolate the formula VIII compound disclosed in patent EP 0 089 167, where R1xe2x95x90R2xe2x95x90Bn. This patent discloses these compounds as prepared xe2x80x9cin situxe2x80x9d (page 8), without any experimental check of their characteristics or chemical structure.
Since the acetoacetates (V) and the benzylidene derivative (VII) are oils, it was fundamental to have a solid intermediate allowing formula (I) compounds to be prepared with a high yield and purity.
The present invention relates to a new compound, ethyl 3-amino-4-(2-(phthalimido)ethoxy)crotonate, of formula III: 
It has been possible to isolate the new compound of formula III in solid state, thereby allowing for the purification, identification and characterisation thereof. This compound has turned out to be very useful as an intermediate for the synthesis of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (of formula I, where NR1R2=phthalimido), the immediate precursor of amlodipine.
The process of preparation of III consists of reacting ethyl 4-[2-(phthalimido)ethoxy]acetoacetate (V, NR1R2=phthalimido) with ammonium acetate in a reaction medium, which is preferably an organic solvent (ethanol, isopropanol, toluene, xylene, etc.) the desired product being obtained in solid state with a good yield and a high degree of purity. The reaction is conducted at a temperature ranging from 10xc2x0 C. to the reflux temperature, preferably from 50 to 70xc2x0 C., and with a Dean-Stark device allowing the water formed in the reaction to be removed. At the end of the reaction, the product was crystallised in an alcohol, being isolated in solid form, the impurities remaining dissolved in the mother liquors. 
One use of interest of the solid ethyl 3-amino-4-(2-(phthalimido)ethoxy)crotonate (of formula III) is achieved by reacting it with methyl 2-(2-chloro-benzylidene)acetoacetate (of formula VII) in a organic solvent (methanol, ethanol, isopropanol, toluene, xylene), preferably ethanol, at a temperature ranging from 10xc2x0 C. and the reflux temperature, preferably from 60 to 80xc2x0 C. The reaction was held for 12 to 24 hours, after which, it was cooled, whereby the 4-(3-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (I; NR1R2=phthalimido) crystallised, and was isolated with a high degree of purity and yield, superior to those described in the literature. 
Certain examples illustrating the invention are described hereinafter.